Investigators Report the Discovery of a Gene Mutation that Causes Atrial Fibrillation

Study in the New England Journal of Medicine implicates a genetic variation that impacts atrial natriuretic peptide.

Mayo Clinic and University of Iowa (UI) researchers report that they have discovered a gene mutation that causes atrial fibrillation. The variation occurs in a gene that encodes a hormone called atrial natriuretic peptide (ANP),which promotes atrial fibrillation.

The study was based on analysis of genetic information from one Caucasian family and control subjects as well as investigations in animal models. “While the family members with atrial fibrillation have a rare mutation, the study findings provide insight into pathways that may be applicable to people in the general population with atrial fibrillation,” according to primary author, Denice Hodgson-Zingman, M.D., assistant professor of internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine.

“Usually inherited arrhythmias are associated with mutations in heart structural proteins or ion channels,” Dr. Hodgson-Zingman continues. “It is intriguing that we identified a circulating hormone as a cause of atrial fibrillation, because this gives us a potential new target for developing treatments.”

The scientists found that the 11 family members with atrial fibrillation had a shared mutation in the gene that encodes for ANP. The mutation was not found in family members without atrial fibrillation or in unrelated patients without the condition.

The research group then used animal models to establish that mutated ANP causes changes in the heart’s electrical function expected to promote atrial fibrillation. They report that this shows that the mutated ANP is not neutral or an incidental finding.

The team also determined that in patients with the mutation, the blood concentration of the abnormal peptide is much higher than that of normal ANP, which is present at typical levels; the mutation is in only one of the two copies of the gene, and thus the people with the mutation also make normal ANP.

Additionally, the study suggests that the mutant peptide appears in the plasma in high levels because it is either not broken down or more of it is generated that normal. “It is more likely that the peptide is not broken down as quickly, but additional research is needed,” says Dr Hodgson-Zingman. “It also is possible that when concentrations are abnormally elevated for long periods of time, they could have toxic effects on the heart.”

The scientists also hypothesize that mutant ANP may be more potent in its cellular effects than nonmutant ANP. “The potency issue is important because it suggests changes to the peptide could be used for therapeutic purposes,” Dr. Hodgson-Zingman adds. “However, more studies would be needed to determine how the peptide binds to receptors and affects downstream mechanisms.”

The results appear online in the July 10 issue of The New England Journal of Medicine.